Adult Summary Report

Secondary Findings in Adult Subjects

Non-diagnostic, excludes newborn screening & prenatal testing/screening

• Status (Adult): Passed (Consensus scoring is Complete)
• Curation Status (Adult): Released - Under Revision
• Status (Pediatric): Incomplete (Consensus scoring is Incomplete)
• GENE/GENE PANEL: GCDH
• Condition: Glutaric Acidemia I
• Mode(s) of Inheritance: Autosomal Recessive

Actionability Assertion

• GCDH ⇔ 0009281 (glutaryl-coa dehydrogenase deficiency): Moderate Actionability

Actionability Rationale

All experts agreed to change the assertion from strong to moderate, as the effectiveness data were extrapolated from pediatric studies and adults are likely to have a milder disease course than children.

Final Consensus Scores

Gene Condition Pairs: GCDH ⇔ 0009281 (OMIM:231670)

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of the Intervention	Total Score
Neurologic crises and functional decline / Low protein/lysine diet	2	2D	0D	2	6DD
Neurologic crises and functional decline / Management by metabolic clinic	2	2D	3D	3	10DD

1. What is the nature of the threat to health for an individual carrying a deleterious allele?

Prevalence of the Genetic Condition

The prevalence of glutaric acidemia I (GA-I) based on newborn screening with tandem mass spectrometry is estimated to be 1.06 per 100,000 births (95% CI: 0.90 to 1.24 per 100,000) in Western populations and 1.40 per 100,000 births worldwide (95% CI: 1.07 to 1.84 per 100,000 births). However, this may be an underestimate as screening may not be able to identify those patients classified as low excretors, as they tend to have normal concentrations of glutarylcarnitines. [1]

Clinical Features

GA-I is a metabolic disorder of lysine metabolism characterized by the accumulation of glutaric acid (GA), 3-hydroxyglutaric acid (3-OH-GA), glutaconic acid, and glutarylcaranitine. Diagnosis of GA-I is confirmed by significantly reduced enzyme activity and/or detection of disease-causing mutations in both GCDH alleles. Two arbitrarily defined biochemical subgroups have been described based on urinary metabolite excretion of GA: low excretors (with up to 30% residual enzyme activity) and high excretors. Both subtypes appear to show a similar clinical course and a high risk of developing striatal injury if untreated.
In neonates and infants, unspecific neurologic symptoms such as muscular hypotonia and delayed motor development occur in about half of all individuals with GA-I, the remaining individuals are asymptomatic. Macrocephaly occurs in approximately 75% of individuals. Untreated, 80-90% of infants will develop neurologic disease during brain development (mainly between 3 and 36 months) following an acute encephalopathic crisis precipitated by illness, vaccination, or surgical intervention. These crises characteristically result in the gradual development of complex movement disorders in the following months and years. Dystonia at rest with action-induced exacerbation, which profoundly interferes with any voluntary movement, is often incapacitating. Dysarthria and dysphagia are also common. Cognitive function in generally considered to be preserved; however comprehensive studies on cognitive functions in GA-I have not been reported. Given the characteristic cerebral abnormalities frequently observed in GA-I and the impact of similar white matter changes observed in other neurologic diseases, individuals with GA-I might be at risk for cognitive dysfunction. In approximately 10-20% of individuals with “insidious onset” type, neurologic disease and striatal injury occur in the absence of encephalopathic crises.
Individuals with the late-onset form of GA-I can present with nonspecific neurologic symptoms such as headaches, vertigo, transient ataxic gait, reduced fine motor skills, or fainting after exercise often presenting in adolescence or adulthood. These individuals do not generally develop striatal injury. Single cases of neoplastic brain lesions have been reported; however, it remains unclear whether these findings are coincidental or whether adults with GA-I have an increased risk of brain neoplasms. A few case reports of previously healthy adolescences and adults developing neurologic signs have been published.
Frequency of epilepsy is increased in patients with GA-I, and seizures may be the initial clinical presentation. GA-I is primarily a neurological disorder; however, recent publications have demonstrated that the peripheral nervous system and kidney disease might also be involved in the long-term disease course. [2, 3, 4]

Natural History

The morbidity and mortality is high for untreated infants and neonates. In contrast, long-term prognosis for individuals diagnosed early appears promising, although mortality rates following the introduction of newborn screening are not yet available. During the last three decades, following the introduction, establishment, and optimization of therapeutic goals for individuals identified through newborn screening, there has been a considerable reduction in the frequency of acute encephalopathic crises and subsequent movement disorders (now 10-20% from 80-90%), and subsequently reduced morbidity and mortality in individuals who are diagnosed early. [2]

2. How effective are interventions for preventing harm?

Patient Management

When GA-I is suspected, diagnostic workup, development of treatment plans, and appropriate information and training of affected individuals and their families should be provided in a specialized metabolic center. For 52 patients identified by newborn screening outcomes were best for those who were cared for under the supervision of a metabolic center were more likely to have care adherent to practice guidelines (35/45) compared to patients not treated through a metabolic center (2/7). In children not followed by a specialized metabolic center movement disorders and encephalopathic crises were more frequent (OR: 10.5 (95% CI: 1.57-70.25)), and morbidity score was higher than in children followed by metabolic centers (p=0.002). (Tier 1) [2]

There is evidence for a correlation of the genotype with biochemical parameters and residual enzyme activity but not with clinical phenotype. Therefore, all diagnosed individuals should receive the same form of maintenance treatment.
• Protein-controlled diet and dietary advice: The effectiveness of dietary treatment after 6 years of age has not been systematically studied. However, as the clinical course is unknown, controlled protein intake using natural protein with a low lysine content and avoiding lysine-rich food is advisable.
• L-carnitine supplementation: Although no randomized controlled studies demonstrate a specific positive effect of L-carnitine on clinical outcomes, L-carnitine supplementation is considered to contribute to reduced risk for striatal injury in individuals diagnosed early and reduced mortality rates in symptomatic individuals with GA-I.
• Adequate supplies of specialized dietetic products and medication required for maintenance and emergency treatment should always be maintained at home. (Tier 2) [2]

Emergency treatment should be considered during severe illness or perioperative management. After age 6 years, the risk for developing an acute crisis is considerably reduced and encephalopathic crises have not been reported; however, the possibility of subclinical cerebral injury cannot be excluded, and the threshold to start emergency treatment should be low in this age group. If alarming symptoms such as recurrent vomiting, recurrent diarrhea, reduced nutrient intake, spiking temperature, or suspicious neurologic signs evolve, individuals should immediately be transferred to the closest hospital or metabolic center to start emergency treatment. Inadequate or delayed start of emergency treatment results in a high risk of striatal injury and dystonia. Written protocols for maintenance and emergency treatment should be regularly updated and provided to all persons involved. An emergency card should be provided summarizing key information and principles of emergency treatment and containing contact information of the treating metabolic center. (Tier 2) [2]

If an elective or emergency surgical intervention is planned, the responsible metabolic center should be informed in advance to discuss perioperative management with surgeons and anesthesiologists. Particular perioperative and intraoperative steps should be taken in individuals with GA-I including:
• Extubation at the end of surgical procedure after the patient is awake and when protective reflexes become present
• Doubling of carnitine dosage
• Limiting of fasting
• Antiemetic prophylaxis
• Monitoring of neuromuscular blockade if neuromuscular blocking agents are used
• Monitoring body temperature
• Consideration of serial intraoperative arterial blood gas analysis for monitoring of pH status, electrolytes, lactate, and glucose levels. (Tier 4) [5]

Individuals with GA-I should be admitted to a hospital and closely monitored after head trauma. Even under recommended treatment and without macrocephaly, subdermal hematoma may occur after minor head trauma. A case report of one child found a subdermal hematoma following minor head trauma in the absence of enlargement of subdural spaces, and therefore subdural hematoma should be considered in any unwell patient after minor accidental head injury. (Tier 2) [2]

Management of pregnancy should be supervised by the responsible interdisciplinary team. Evidence and/or sufficient clinical experience regarding efficacy or necessity of emergency treatment during the peripartum period is not available. However, for surgical procedures (e.g., C-section), recommendations for perioperative management should be regarded as valid. Uneventful clinical course for mother and child has been reported for women receiving emergency treatment during the peripartum period as well as women who did not receive any specific treatment.
• In the case of a 23-year-old woman with a history of GA-I diagnosed in infancy, management during pregnancy included continued protein restriction, echocardiogram, biochemical monitoring, and increased carnitine supplementation. A successful C-section was performed with reduced perioperative fasting and perioperative infusion of L-carnitine. The woman remained asymptomatic and was discharged home on the third postoperative day.
• One woman with a two uneventful pregnancies and deliveries had been followed from 15 months to 10 years for learning disabilities; however, she had graduated from school with special teaching support. She was identified as having GA-I following newborn screening in her second child. The physical examination of the mother was unremarkable except for a moderate mental deficit. Elevated GA and 3-OHGA were identified in urine and gene testing showed two heterozygous mutations in the GCDH gene.
• One woman presented at age 8 with macrocephaly, mild developmental delay, and epilepsy. At age 20 she had an uneventful pregnancy and delivery. Antiepileptic medications were modified, however she received no carnitine supplementation. (Tier 2) [2]

Surveillance

Therapeutic effectiveness should be monitored by regular follow-up and intensified at any age if symptoms progress, new symptoms manifest (disease- or therapy-related), or nonadherence to treatment recommendations is suspected. Yearly clinical monitoring should include clinical history, anthropometrics, clinical examination, neurologic assessment, specific psychological tests, dietary assessment, biochemistry (i.e., plasma amino acids, carnitine, and kidney function), quality of life, and psychological counseling (on request). Because urinary concentrations of GA and 3-OH-GA do not correlate with clinical parameters, analysis of urinary concentrations of GA and 3-OH-GA should not be used for treatment monitoring. (Tier 2) [2]

Neuroradiologic investigation should be performed if signs or neurologic deterioration occur. Neurologic (i.e., epilepsy, movement disorder) or neurosurgical complications should be managed by a neurologist and/or neurosurgeon in close cooperation with a metabolic specialist. While diagnosis made after manifestation of neurologic disease is associated with a limited therapeutic impact, some affected individuals may benefit by prevention of progressive neurologic deterioration. In general, treatment of movement disorder associated with GA-I is challenging, with little evidence regarding the effectiveness of specific drugs. Potential treatments include: baclofen, benzodiazepines, anticholinergics, and botulinum toxin. No study has analyzed the effectiveness of antiepileptic agents in GA-I; however, valproate and vigabatrin should be avoided. (Tier 2) [2]

Circumstances to Avoid

Avoiding lysine-rich food is advisable. (Tier 2) [2]

Valproate and vigabatrin should be avoided; vigabatrin may induce peripheral visual field defects as a putative side effect and valproate may negatively affect acetyl-CoA/CoA ratio. (Tier 2) [2]

Reports that propofol can cause lipid overload and inhibit oxidative phosphorylation, carnitine palmitoyltransferase transport of long-chain fatty acids, and β-oxidation of fatty acids in mitochondria raise concerns about the possibility of occurrence of propofol infusion syndrome and severe metabolic acidosis. Long procedures with total intravenous anesthesia with propofol are probably not advisable. There are reports of use of thiopentone for induction without complications. (Tier 4) [5]

Intraoperatively Ringer’s lactate should be avoided since it contains lactic acid. (Tier 4) [5]

3. What is the chance that this threat will materialize?

Mode of Inheritance

Autosomal Recessive

Prevalence of Genetic Variants

No information the prevalence of genetic mutations was identified.

Penetrance

An international registry included 150 individuals with GA-I diagnosed via onset of symptoms, newborn screening, or metabolic cascade testing in high-risk families. Median age at diagnosis was 270 days; however, some outlier patients were diagnosed as adults. Of these 150, 3 individuals were classified as having early onset disease (having a neonatal crisis at ≤28 days), 48 individuals as having late onset disease (crisis after 28 days), 26 individuals with late onset disease without an acute crisis, and 73 of 150 patients were classified as asymptomatic. Of the symptomatic individuals the median age at onset of symptoms was 300 days (IQR: 145-428) with 51 individuals presented with an encephalopathic crisis as the initial clinical manifestation. Of the 74 late-onset patients, 12 showed epilepsy as the initial clinical presentation and 29 presented with dystonic movement disorders without preceding encephalopathic crisis.
Overall, neurologic manifestations of GA-I (including those with crisis during the newborn period) included: decreased muscle strength (28%), muscular hypotonia (25%), muscular hypertonia (17%), abnormal gross motor development (40%), abnormal fine motor development (46%), disturbed balance (39%), movement disorder (46%), seizures (7%), and EEG abnormalities (34%). Arterial hypertension was observed in 3 of patients. (Tier 3) [6, 7]

Relative Risk

No information on relative risk was identified.

Expressivity

No information on expressivity was identified.

4. What is the Nature of the Intervention?

Nature of Intervention

Interventions for GA-I may include: limiting dietary protein, supplementation with L-carnitine, management during pregnancy and emergency setting, avoidance of medications, avoidance of fasting, and biochemical and neurologic monitoring. Use of oral L-carnitine may be associated with diarrhea and a fishy odor. [2]

5. Would the underlying risk or condition escape detection prior to harm in the setting of recommended care?

Chance to Escape Clinical Detection

The screen-detected prevalence is much higher than the prevalence based on clinical detection in Western countries (1.06 versus 0.28 per 100,000) and worldwide (1.40 versus 0.35 per 100,000). Under-ascertainment by clinical diagnosis is likely, due to the heterogeneous clinical presentation of GA-I. (Tier 1) [1]

Date of Search: 09.19.2017

Reference List

1. Moorthie S, Cameron L, Sagoo GS, Bonham JR, Burton H. Systematic review and meta-analysis to estimate the birth prevalence of five inherited metabolic diseases. J Inherit Metab Dis. (2014) 37(6):889-98.

2. Boy N, Muhlhausen C, Maier EM, Heringer J, Assmann B, Burgard P, Dixon M, Fleissner S, Greenberg CR, Harting I, Hoffmann GF, Karall D, Koeller DM, Krawinkel MB, Okun JG, Opladen T, Posset R, Sahm K, Zschocke J, Kolker S. Proposed recommendations for diagnosing and managing individuals with glutaric aciduria type I: second revision. J Inherit Metab Dis. (2017) 40(1):75-101.

3. Glutaryl-CoA dehydrogenase deficiency. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=25

4. C Klein, C Marras, A M?nchau. Dystonia Overview. 2003 Oct 28 [Updated 2014 May 01]. In: RA Pagon, MP Adam, HH Ardinger, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1155

5. Martins, P; Sung CS; Janssen M. Anaesthesia recommendations for patients suffering from Glutaric acidemia type 1. orphananesthesia. (2016) Accessed: 2017-09-19. Website: https://www.orpha.net/data/patho/Ans/en/GlutaricAcidemiaType1_PT_en_ANS_ORPHA25.pdf

6. Kolker S, Garcia-Cazorla A, Valayannopoulos V, Lund AM, Burlina AB, Sykut-Cegielska J, Wijburg FA, Teles EL, Zeman J, Dionisi-Vici C, Baric I, Karall D, Augoustides-Savvopoulou P, Aksglaede L, Arnoux JB, Avram P, Baumgartner MR, Blasco-Alonso J, Chabrol B, Chakrapani A, Chapman K, I Saladelafont EC, Couce ML, de Meirleir L, Dobbelaere D, Dvorakova V, Furlan F, Gleich F, Gradowska W, Grunewald S, Jalan A, Haberle J, Haege G, Lachmann R, Laemmle A, Langereis E, de Lonlay P, Martinelli D, Matsumoto S, Muhlhausen C, de Baulny HO, Ortez C, Pena-Quintana L, Ramadza DP, Rodrigues E, Scholl-Burgi S, Sokal E, Staufner C, Summar ML, Thompson N, Vara R, Pinera IV, Walter JH, Williams M, Burgard P. The phenotypic spectrum of organic acidurias and urea cycle disorders. Part 1: the initial presentation. J Inherit Metab Dis. (2015) 38(6):1041-57.

7. Kolker S, Valayannopoulos V, Burlina AB, Sykut-Cegielska J, Wijburg FA, Teles EL, Zeman J, Dionisi-Vici C, Baric I, Karall D, Arnoux JB, Avram P, Baumgartner MR, Blasco-Alonso J, Boy SP, Rasmussen MB, Burgard P, Chabrol B, Chakrapani A, Chapman K, Cortes I Saladelafont E, Couce ML, de Meirleir L, Dobbelaere D, Furlan F, Gleich F, Gonzalez MJ, Gradowska W, Grunewald S, Honzik T, Horster F, Ioannou H, Jalan A, Haberle J, Haege G, Langereis E, de Lonlay P, Martinelli D, Matsumoto S, Muhlhausen C, Murphy E, de Baulny HO, Ortez C, Pedron CC, Pintos-Morell G, Pena-Quintana L, Ramadza DP, Rodrigues E, Scholl-Burgi S, Sokal E, Summar ML, Thompson N, Vara R, Pinera IV, Walter JH, Williams M, Lund AM, Garcia-Cazorla A. The phenotypic spectrum of organic acidurias and urea cycle disorders. Part 2: the evolving clinical phenotype. J Inherit Metab Dis. (2015) 38(6):1059-74.